RESEARCH ARTICLE CIC Inactivating Mutations Identify Aggressive Subset of 1p19q Codeleted Gliomas Vincent Gleize, PhD, 1 Agusti Alentorn, MD, PhD, 1,2 L ea Connen de K erillis, MSc, 1 Marianne Labussie ` re, PhD, 1 Aravidan A Nadaradjane, BSc, 1 Emeline Mundwiller, MSC, 3 Chris Ottolenghi, MD, PhD, 4 Stephanie Mangesius, MSc, 1 Amithys Rahimian, MSc, 5 Franc ¸ois Ducray, MD, PhD, 6 on behalf of the POLA network, Karima Mokhtari, MD, 1,5,7 Chiara Villa, MD, 7 and Marc Sanson, MD, PhD 1,2,5 Objective: CIC gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, clinical and biological impact remain poorly understood. Methods: We sequenced the CIC gene on 127 oligodendroglial tumors (109 with the 1p19q codeletion) and ana- lyzed patients’ outcome. We compared magnetic resonance imaging, transcriptomic profile, and CIC protein expres- sion of CIC wild-type (WT) and mutant gliomas. We compared the level of expression of CIC target genes on Hs683- IDH1 R132H cells transfected with lentivirus encoding mutant and WT CIC. Results: We found 63 mutations affecting 60 of 127 patients, virtually all 1p19q codeleted and IDH mutated (59 of 60). In the 1p19q codeleted gliomas, CIC mutations were associated with a poorer outcome by uni- (p 5 0.001) and multivariate analysis (p < 0.016). CIC mutation prognostic impact was validated on the TCGA cohort. CIC mutant grade II codeleted gliomas spontaneously grew faster than WTs. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell gene expression profile in CIC mutant gliomas, with upregulation of normally CIC repressed genes ETV1, ETV4, ETV5, and CCND1. Various missense mutations resulted in CIC protein expression loss. Moreover, a truncating CIC mutation resulted in a defect of nuclear targeting of CIC protein to the nucleus in a human glioma cell line expressing IDH1 R132H and overexpression of CCND1 and other new target genes of CIC, such as DUSP4 and SPRED1. Interpretation: CIC mutations result in protein inactivation with upregulation of CIC target genes, activation of prolif- erative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted glioma. ANN NEUROL 2015;78:355–374 G liomas are highly invasive, mostly chemoresistant tumors. They are classified according to their malignancy grade and glial cell line phenotype into astro- cytomas (grade I to IV, known as glioblastoma), oligo- dendrogliomas (grade II or III), and oligoastrocytomas (grade II to IV, known as glioblastoma multiform with oligodendroglial component). 1 The prognosis is not only determined by tumor grade, but also by genetic profile. This is particularly true for anaplastic oligodendroglio- mas, whose median survival ranges from 2 to 14 years, depending on the genetic profile. 2 The combined loss of one copy of chromosome arms 1p and 19q (1p19q codeletion) resulting from an unbalanced translocation affects 60% to 80% of oligo- dendrogliomas and 10% to 15% of oligoastrocytomas. This genetic alteration is associated with a better View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24443 Received Nov 13, 2014, and in revised form May 25, 2015. Accepted for publication May 26, 2015. Address correspondance to Dr Marc Sanson, Service de Neurologie 2, Groupe Hospitalier Piti  e-Salp^ etrie ` re, 75651, Paris cedex 13, France. E-mail: marc.sanson@psl.aphp.paris.fr From the 1 Sorbonne Universit e, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France; 2 AP-HP, Groupe Hospitalier Piti  e-Salp^ etrie ` re, Service de Neurologie 2, Paris, France; 3 Institut du Cerveau et de la Moelle Epinie ` re, Plateforme de G enotypage et S equenc ¸age, Paris, France; 4 Biochimie M etabolique, Universit e Paris Descartes et Inserm U1124, Paris, France; 5 AP-HP, Onconeurothe ` que, Paris, France; 6 H^ opital Neurologique, Service de Neurologie B, Lyon, France; and 7 AP-HP, Groupe Hospitalier Piti  e Salp^ etrie ` re, Laboratoire de Neuropathologie R Escourolle, Paris, France V C 2015 American Neurological Association 355